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Monday, 5 October 2015

(WO2015139602) Sofosbuvir New Patent

(WO2015139602) 2'-SUBSTITUTED-2,2'-DEHYDRATED URIDINE OR 2'-SUBSTITUTED-2,2'-DEHYDRATED CYTIDINE COMPOUND AND PREPARATION METHOD AND USE THEREOF

ZHANG, Rongxia

A further object of the present invention to provide a method for preparing a compound of formula I.

The present invention provides a process for preparing a compound I 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'-fluoro-cytidine using the following formula or 2'-deoxy-2'-substituted 2'-2'-substituted nitrile or uridine 2'-deoxy-2'-substituted-2'-carbonitrile The method of cytidine compound,

Sofosbuvir developed by Gilead Science Company, FDA on December 6, 2013 Sofosbuvir formally approved for the treatment of chronic hepatitis C virus (HCV) infection. Sofosbuvir is first used to treat certain types of HCV infection without the use of interferon effective and safe drugs. Clinical trials have shown, sofosbuvir can achieve very high proportion of sustained virologic response (clinical cure). More revolutionary breakthrough that, sofosbuvir without joint peginterferon α situation is still very significant effect, such as sofosbuvir ribavirin genotype 2 and genotype 3 patients with previously untreated chronic hepatitis C continued virological response rate of 100%. Sofosbuvir is a prodrug is metabolized in vivo to 2'-deoxy-2'-fluoro-2'-methyl-uridine-5'-monophosphate.

Currently reported 2'-deoxy-2'-fluoro-2'-methyl uridine synthetic methods are as follows:

In the literature (Journal of Medicinal Chemistry, 2005,48,5504) in order cytidine as a raw material, first selectively protected 3 ', 5'-hydroxyl group, and then oxidizing the 2'-hydroxyl to a carbonyl group, and the reaction of methyllithium get the 2'-hydroxyl compound, and then removing the protective group, use benzoyl protected 3 ', 5'-hydroxyl group, and then reacted with DAST fluorinated compound, followed by hydrolysis and aminolysis reaction products, such as the following Reaction Scheme. The method of route length, the need to use expensive silicon ether protecting group molecule relatively poor economy; conducting methylation time will generate a non-methyl enantiomer beta bits.

In Patent (WO2005003147, WO2006031725A2, US20040158059) using 2'-fluoro-2'-methyl - ribose derivative with N- benzoyl cytosine for docking the reaction, then after the hydrolysis, aminolysis reaction to obtain the final product, As shown in the following reaction scheme. Raw material of the process is not readily available, synthetic steps cumbersome, expensive; the reaction product obtained contained docking base for the alpha position isomers, need purification removed to form waste.

SUMMARY OF THE INVENTION

The present inventors have designed and synthesized a compound of formula I as shown, the compound may be a fluorinated or nitrile reaction of 2'-deoxy-2'-fluoro-2'-get-substituted uridine or 2 under appropriate conditions' - 2'-deoxy-2'-fluoro-2'-deoxy-2'-substituted cytidine or nitrile uridine or 2'-substituted-2'-deoxy-2'-substituted-2'-cytidine nitrile compound; or a compound of formula I or a nitrile group by fluoro reaction, followed by deprotection reaction to give 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'-fluoro--2 '- cytidine or 2'-substituted-2'-deoxy-2'-nitrile-substituted uridine or 2'-deoxy-2'-substituted-2'-cytidine compound nitrile group; or a compound of formula I through the opening cyclization reaction, and then through the group of fluoro or nitrile, and finally deprotection reaction to give 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'-fluoro-2'-substituted Cellular glycoside or 2 'substituted-2'-deoxy-2'-carbonitrile 2'-deoxy-uridine or 2'-substituted-2'-cytidine compound nitrile group; or a compound of formula I through a ring-opening reaction, and then 2 '- hydroxyl forming a leaving group, and then after a nitrile group or a fluorinated reaction, the final deprotection reaction of 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'- cytidine or 2'-fluoro-2'-substituted-2'-deoxy-2'-nitrile-substituted uridine or 2'-deoxy-2'-substituted-2'-cytidine nitrile compound.

It is therefore an object of the present invention is to provide a compound of the general formula I prepared 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'-fluoro-2'-substituted cytidine or 2'-substituted-2'-deoxy-2'-carbonitrile uridine or 2'-deoxy-2'-substituted-2'-carbonitrile The method of cytidine compound.

The compound of Example 1 Ia (0.24g, 1mmol)) was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure, the residue was added acetone, beating, and filtered to give solid (0.18g, yield: 70%).

Compound Ib (0.45g, 1mmol) was dissolved in a mixture of dichloromethane and pyridine, was added DAST (0.32g), stirred for 24 hours, added dichloromethane (20ml) was diluted with water (30ml × 2), dried over anhydrous dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the residue was subjected to column chromatography to give the product (0.36g, yield: 78%).

The compound of Example 3 IIa (0.47g, 1mmol) dissolved in 10% methanol solution of ammonia and stirred overnight, the solvent was removed under reduced pressure, and the residue was slurried in ethyl acetate, filtered to give a white solid (0.2g, yield : 77%).

Compound IVa (0.57g, 1mmol) was dissolved in dichloroethane (20ml) was added trifluoromethanesulfonic acid trimethylsilyl ester (1ml), was heated for 12 hours, cooled, and the reaction solution was concentrated dryness, added two dichloromethane (100ml) was dissolved, washed successively with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give an oil which was purified by column chromatography to give a white solid (0.3g, yield : 67%).

The compound of Example 6 Ic (50mg, 0.122mmol) was dissolved in methanol (1ml) was added 1N sodium hydroxide solution (0.2ml), stirred at room temperature overnight, water was added and the methylene chloride solution was separated, the organic layer was concentrated after purified by column chromatography to give the product (45mg, yield: 87%).

The 2'-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added N, N'- carbonyldiimidazole (0.194g, 1.2mmol) and sodium bicarbonate (55mg, 0.66mmol), was heated to 130 ℃, stirred for 4 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled, The solvent was removed under reduced pressure, the residue was added to acetone and filtered to obtain a solid IIIa (0.12g, yield: 60%).

Example 11:

The 2'-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added diphenyl carbonate (0.256g, 1.2mmol) and sodium bicarbonate ( 55mg, 0.66mmol), was heated to 150 ℃, stirred for 6 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure The residue was added to acetone and filtered to obtain a solid IIIa (0.13g, yield: 65%).

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DR ANTHONY MELVIN CRASTO Ph.D , Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues,

Currently he is working with GLENMARK- GENERICS LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India.

Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now Sanofi Aventis, & Searle India ltd, now Rpg lifesciences, etc. He has worked in Basic research, Neutraceuticals, Natural products, Flavors, Fragrances, Pheromones, Vet Drugs, Drugs, formulation, GMP etc. He has total 25 yrs exp in this field, he is now helping millions, has million hits on google on all organic chemistry websites.

He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 25 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide .

He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

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DR ANTHONY MELVIN CRASTO,WorldDrugTracker, helping millions, A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, This will not stop meDR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution

Dr. Anthony Melvin Crasto, graduated from Mumbai University, Completed his Ph.D from ICT, 1991, Mumbai, India, in the field of Organic Chemistry, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as a Principal Scientist, in Process Research at Mahape, Navi Mumbai, India, for the last 10 years, His total Industry experience is 30 +yrs with major Multinationals companies.

Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable Scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri , Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did Custom Synthesis for various multinationals in his career like BASF, Novartis, Sanofi, Pfizer etc., He has worked in Drug Discovery, Natural products, Bulk Drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, Pharma Plant, API plant etc, he is now helping millions, His friends call him worlddrugtracker.

His New Drug Approvals, All about drugs, Eurekamoments, Organic spectroscopy international,etc in Organic/ Medchem are some most read blogs. He has hands on experience in initiation and developing Novel routes for Drug molecules and implementing them on commercial scale over a 30 year tenure till date Feb’ 2018, Around 30 plus commercial products in his career. He has good knowledge of IPM, GMP, QbD, Regulatory aspects, Technology transfer, Manufacturing, Formulations, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc. He has several International patents published worldwide.

He suffered a one in a million disease in the form of a paralytic stroke/ Acute Transverse Mylitis in Dec’ 2007 and is 90 % paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, he has several million hits on Google, 60 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto

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DR ANTHONY MELVIN CRASTO Ph.D , Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues,

Currently he is working with GLENMARK PHARMA LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India.

Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now Sanofi Aventis, & Searle India ltd, now RPG lifesciences, etc. He has worked in Basic research, Neutraceuticals, Natural products, Flavors, Fragrances, Pheromones, Vet Drugs, Drugs, formulation, GMP etc. He has total 30 yrs exp in this field, he is now helping millions, has million hits on google on all organic chemistry websites.

He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide .

He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has 2.5 lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com, Twitter @amcrasto